Cell Microenvironment and Progression of Breast Cancer

Institution: Lawrence Berkeley National Laboratory
Investigator(s): Andre Lochter, Ph.D. -
Award Cycle: 1995 (Cycle I) Grant #: 1FB-0391 Award: $66,048
Award Type: Postdoctoral Fellowship
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease

Initial Award Abstract (1995)
Progression of breast cancer from benign cells to a life-threatening disease is characterized by acquisition of migratory and invasive properties of tumor cells as they move through the breast tissue in search of blood vessels. It is this process and the subsequent infiltration of blood vessels and colonization of other organs which constitutes metastasis. From our own past and ongoing research, and from published reports, we have concluded that a major factor in tumor progression is the interaction of tumor cells with their surrounding microenvironment. This microenvironment consists of stroma, cells that create a supporting framework which is often composed of connective tissue for a gland or organ, and extracellular matrix (ECM), the interwoven network of proteins which provides additional support and vital information to surrounding cells.

It is known that for normal functioning, cells require the surrounding structure of the ECM. Although attempts have been made to understand the interaction of the cell with its microenvironment, the lack of suitable tissue culture models has hampered the precise interpretation of the data obtained and raised questions about their physiological relevance. We have now begun to reconstitute the cellular and ECM microenvironment of tumor cells in three dimensions by taking into culture a cell line which recapitulates the different stages of tumor progression. With this designer microenvironment in hand, we are able to analyze the role of tumor cell-stroma interactions and molecules of the ECM in tumor progression and to test our hypotheses by experimental manipulation. In our investigation, we will focus on a class of matrix-degrading enzymes, metalloproteinases, which are frequently found in large amounts in breast tumors, and are believed to promote tumor cell invasion by breaking down the components of ECM.

The proposed study is expected to enable a better understanding of the development of breast cancer and to identify molecular changes associated with the early stages of tumor progression in the breast. Detection of these changes in tumor patients would thus provide a valuable tool for the diagnosis of breast cancer. Furthermore and foremost, we expect to identify those molecules which are indispensable for tumor migration and invasion. By interfering with their function we hope to block tumor progression. We will also search for signals inside the ECM which attenuate or abolish tumor progression. Upon identification of these inhibitory signals we will engineer small peptides (chains of amino acids) which can be administered to breast tissues and block tumor progression.

Final Report (1998)
The objective of the project was to analyze the role of molecules that are secreted by breast tumor cells and that digest other molecules located outside or on the surface of cells in the initiation and progression of breast cancer. The study has focused particularly on the involvement of these matrix metalloproteinases (MMPs) in the establishment of a tumor phenotype, and on the regulation of their synthesis by tumor cells. It was discovered that a particular MMP enzyme, stromelysin-l, can initiate a cascade of events that culminates in production of an invasive tumor cell phenotype in normal, non-tumorigenic and non-invasive cells. Stromelysin-1 could trigger the gradual acquisition of such phenotype in the absence of random genetic mutations by a process we call "epigenetic programming". It was also found that members of another class of molecules that is found outside of the cell, the extracellular matrix molecules, plays a key role in regulating stromelysin-1 expression in tumor cells. In addition, we studied two breast cancer cell surface receptors, called 'integrins' that interact with the extracellular matrix. These 'integrins' are also critical modulators of stromelysin-1 expression. Finally, it was found that interfering with the function of these two 'integrin receptors' could prevent certain aspects of stromelysin-l-dependent malignant tumor cell behavior. The novel concept of "epigenetic programming" of cells to develop breast tumor-like properties upon exposure to MMPs, and the pivotal function of extracellular matrix molecules and their receptors in regulating MMP synthesis, has profound implications for the etiology of breast cancer and also for its diagnosis and prevention. Due to both new R&D of specific synthetic inhibitors for MMPs and the diagnostic reagents that can detect these enzymes, additional information on the molecules that regulate their expression will provide new clues for the prognosis and treatment of breast cancer.

Tissue structure- the ultimate regulator of cell function?
Periodical:Philosophical Transactions of the Royal Society of London Series B: Biological Sciences
Index Medicus: Philos Trans R Soc Lond B Biol Sci
Authors: Hagios C, Lochter A, Bissell MJ
Yr: 1998 Vol: 353 Nbr: Abs: Pg:857-870

The significance of matrix metalloproteinase during the early stages of tumor progression
Periodical:Annals of the New York Academy of Sciences
Index Medicus: Ann N Y Acad Sci
Authors: Lochter A, Sternlicht MD, Werb Z, Bissell MJ
Yr: 1998 Vol: 857 Nbr: Abs: Pg:180-93

Matrix metalloproteinase stromelysin-1 triggers a cascade of molecular alterations that leads to stable epithelial-to-mesenchymal conversion and a premalignant phenotype in mammary epithelial cells
Periodical:Journal of Cell Biology
Index Medicus: J Cell Biol
Authors: Lochter A, Galosy S, Muschler J, Freedman N, Werb Z, Bissell MJ
Yr: 1997 Vol: 139 Nbr: 7 Abs: Pg:1861-72